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Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents

W Xu1, L Liu, G C Smith

  • 1The Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, UK.

Nature Cell Biology
|June 15, 2000
PubMed

Insights

Nitric oxide (NO) increases DNA-dependent protein-kinase catalytic subunit (DNA-PKcs) expression, enhancing DNA repair. This boosts cell protection against NO and DNA-damaging agents like X-rays and chemotherapy drugs.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Nitric-oxide synthase (NOS) activity is observed in human tumors, but its precise role remains elusive.
  • The function of nitric oxide (NO) in cellular processes, particularly DNA repair, requires further elucidation.

Purpose of the Study:

  • To investigate the effect of nitric oxide (NO) on the expression of DNA-dependent protein-kinase catalytic subunit (DNA-PKcs).
  • To determine if NO-induced DNA-PKcs enhances cellular protection against DNA-damaging agents.

Main Methods:

  • Cellular exposure to nitric oxide (NO).
  • Quantification of DNA-dependent protein-kinase catalytic subunit (DNA-PKcs) expression.
  • Assessment of cellular protection against NO and various DNA-damaging agents (X-ray radiation, adriamycin, bleomycin, cisplatin).

Main Results:

  • Nitric oxide (NO) exposure led to a significant 4-5 fold increase in DNA-dependent protein-kinase catalytic subunit (DNA-PKcs) expression.
  • The elevated levels of enzymatically active DNA-PK conferred protection to cells against the toxic effects of NO.
  • This NO-mediated increase in DNA-PKcs provided cross-protection against clinically relevant DNA-damaging agents.

Conclusions:

  • Nitric oxide (NO) upregulates DNA-dependent protein-kinase catalytic subunit (DNA-PKcs), a key enzyme in double-stranded DNA break repair.
  • This represents a novel and potent NO-mediated DNA repair mechanism.
  • The findings suggest a new therapeutic avenue involving NO modulation for enhancing cancer treatment efficacy.

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